by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
On January 5-6, 2000, the Office of Dietary Supplements, a branch of the National Institutes of Health, and the Life Sciences Research Office of the American Society of Nutritional Sciences held a conference/workshop entitled “The Bioavailability of Nutrients and Other Bioactive Components of Dietary Supplements: Defining the Research Agenda.” Courtesy of The Power Store I was fortunate enough to attend this workshop, and this article represents a review of the conference.
The Definitional Challenge
Try to define bioavailability. Since you’re reading this article, I’ll save you some time. Taber’s Cylopedic Medical Dictionary 18th edition defines bioavailability as “ the rate and extent to which an active drug or metabolite enters general circulation, permitting action to the site of action. Bioavailability is determined either by measurement of the concentration of the drug in body fluids or by the magnitude of the pharmacologic response.” This seems fairly well defined. However, consider that fiber (not a drug or metabolite) doesn’t enter your blood and in normal dosages doesn’t cause a pharmacologic effect. Next, consider a vitamin pill, which contains all the essential vitamins. After you swallow the pill, blood levels of some vitamins increase rapidly. Other vitamins don’t increase at all. If we check your urine a few hours from now, we find that most of the water-soluble vitamins are being rapidly excreted. If we just checked your blood levels of these vitamins, we might say that some are very well absorbed and hence have a good bioavailability. Now that we see they are excreted rapidly, we realize that the body doesn’t have a chance to utilize and/or metabolize them since they are excreted so quickly. The time period is too short, so we can’t detect any physiological effects, and the dosages are too low, so there won’t be any pharmacological effects. Given the many different ways substances interact in the body at specific times, it seems almost impossible to define bioavailability. And to our dismay, bioavailability gets even more complicated. Let’s say we define it for a given nutrient. Pick zinc for an example. Suppose we use it in a formula with other minerals. Well, everything we just learned about zinc by itself may no longer be applicable because other nutrients can interfere with the zinc. Now let’s change the delivery system. We can use a hard tablet, powder-filled capsule, liquid, or lozenge. All these delivery methods change the absorption and excretion of the nutrient to the body and hence can impact our findings. It seems that in order to define bioavailability for dietary supplements, several factors need to be considered. These include digestion, absorption, metabolism, excretion, utilization, and physiological effect. Additionally, considerations must be given to the type of delivery system, whether or not the supplement is administered alone or in combination with other supplements, and the impact of storage.
Bioavailability and DSHEA
Starting a discussion of bioavailability is the equivalent of opening up the proverbial can of worms. Because there is no common consensus definition, it can’t be regulated. Nobody can agree on what bioavailability means. Let’s start this off by relating the term to DHSEA. DSHEA is the acronym for the Dietary Supplement Health and Education Act. This act provides that dietary supplements are regulated under food provisions of the Food, Drug, and Cosmetic Act. Drug regulation has formal guidelines and published regulations that define bioavailability. The FDA’s food supplement regulatory framework has none of the above. Historically, food supplements have been regulated on a case-by-case basis. According to Elizabeth Yetley, Ph.D., “The FDA has incorporated bioavailability requirements into food additives, GRAS (Generally Recognized as Safe) reviews, label claims, infant formulas, and more.” How has this impacted you, the consumer? Take, for example, Oelstra. It is considered a non-absorbable food additive used in place of fat. Ingestion of Olestra may lower the absorption of fat-soluble vitamins such as A, D, E, and K. Therefore, additional fat-soluble vitamins are added to this product and this information must be on food labels. From this example, bioavailability is based off absorption of fat -soluble nutrients. However, GRAS nutrients may not exceed the amounts necessary to produce a desired effect. In this case, bioavailability is based off a physiological effect. So you can see the confusion not having a common definition for bioavailability creates. After a definition can be agreed upon, products need to be appropriately labeled and the labels should accurately reflect label claims. This also raises separate issues, such as how do we monitor compliance by companies, and how do they substantiate their claims?
Dietary Supplements: Whose Taking Them?
The purpose of the seminar was to define the research agenda so that scientists could provide the necessary information to health policy makers who could then produce guidelines for consumers. Critiques raised against supplement research included the slow release of information and lack of application and studying the wrong supplements (ie no one is taking them). In order for scientists to generate information that has application to consumers, they need to know what the popular supplements are. In order to make a health policy like the RDA, a variety of data is needed. This includes data on food intakes, studies with multiple intakes and measured indicators of adequacy, indicators that reflect status of the individual, indicators correlated with health or functional outcome, and both a half-way point and coefficient of variation of requirements needed to establish an estimated average requirement.
Janet Greger, Ph.D. provided some interesting information about supplement users. Overall, people are now taking charge of their health and are moving in a proactive direction by trying to prevent poor health and disease. This is a transition from years ago where people would respond in a reactive fashion (they would do something after they got sick). Dietary supplement sales increased to almost 8 billion dollars in 1996. That is some serious money. Thirty-five percent of people surveyed in the US report taking herbal supplements and 54% report supplement use in general. Characteristics of supplement users include a tendency to be Caucasian, female, older, educated beyond high school, and have a greater than average income. Surprisingly however, they do not know more about nutrition than other groups. Supplement users also ingest less alcohol, don’t smoke, consume more fruits and vegetables, tend to be less overweight, consume more nutrient dense diets, and exercise more then their non-supplement using counterparts. All of these factors are associated with decreased risks for a variety of diseases, which only complicates interpretation of the impact of dietary supplement use. The nutrients most often ingested in exceedingly high quantities include thiamin, riboflavin, Vitamin E, Vitamin C, Vitamin B12, Vitamin B6, niacin, Vitamin A, and iron. I don’t know about you, but my initial thoughts are what about whey protein, creatine, MRPs, protein bars, and ephedrine containing products? It seems everyone I know takes these supplements and they weren’t even mentioned. This illustrates that there are serious gaps between what scientists think is being ingested and what is actually being ingested.
Bioavailability Assumptions for Daily Recommended Intakes (DRIs)
I’m won’t bore you to death and cover all of the nutrients here. I am going to cover just a few so you have an idea of the issues involved when using a poorly defined term. In order to calculate the bioavailability of Vitamin B12 for determining the DRIs, additional factors were considered besides the form (ie supplement or food component) like factors that affect absorption/utilization and assumption of a “typical” diet. First the assumptions were made that normal gastric, pancreatic, and ileal functions are present. Next a 50% average absorption for all forms of B12 was estimated. Then an allowance was made for the fact that 10–30% of people greater than 50 years of age have atrophic gastritis (meaning they cannot produce the intrinsic factor necessary to absorb B12). There are several flaws in this approach. Not everyone has an intact stomach, and/or functional pancreas and ileum, or produces sufficient intrinsic factor. Defining the bioavailability of this nutrient is difficult because the various tissues and factors involved can be impaired quite easily by a variety of diseases.
Ever hear someone say how food is much better than supplements or that they take something because it is “natural”? Well, now is your chance to gather some information to fire back at them. The synthetic form of folate is the perfect example. Synthetic folate is absorbed 1.7-2.0 times better than food folate. Folate supplements with water are absorbed more completely than when taken with food. Previous folate intakes were inaccurate due to underreporting errors, inadequate enzymatic digestion of the food folate, data on intake based on pre-fortification values for folate content in foods consumed, and the folate content of foods is not always available in dietary folate units. Defining the bioavailability of this nutrient depends on the form, synthetic vs natural, and what it is ingested with.
Iron is an important mineral that has been researched extensively. What is unique about this nutrient is that the body can regulate its absorption based upon need, so absorption can increase when there is an increased need. Iron from animal food sources is often in the heme form, which is absorbed far better than iron from plants or supplements in the non-heme form. Ascorbic acid (Vitamin C) can increase the absorption of iron, while phytate and fiber can decrease the absorption of iron. Defining the bioavailability of this nutrient is difficult because so many dietary factors can influence its absorption.
In summary, bioavailability is not well defined. Historically the FDA has used various definitions on a case-by-case basis. Factors to consider for defining bioavailability are digestion, absorption, metabolism, excretion, utilization, and physiological effect. There is debate whether supplements and other food additives be considered on a case-by-case basis, separate category, or some other basis.
Measurement of Bioavailability
Dr Srinivasan from the United States Pharmacopeia presented an interesting lecture. In order for nutrients to be absorbed into the body, they must be in solution. This means they must dissolve. The USP studies bioavailability by using simple index nutrients in dissolution studies. By purchasing and ingesting your multiple vitamin/mineral tablet with the USP logo on the label, you may be thinking that all the nutrients are present in the product and guaranteed to be absorbed. In actuality only two nutrients, riboflavin and iron are usually tested. The index vitamin approach is only valid for the water-soluble vitamins, like vitamin C and the B vitamins. Of these, riboflavin (B2) is the least absorbed and hence the vitamin of choice for testing the supplement. Since iron deficiency is the most common deficiency in this country, it is usually the index mineral used. The assumption here of course is that the supplement contains riboflavin and iron. If it does not then other index nutrients may be used. To test for bioavailability, the multiple vitamin/mineral supplement is placed in a flask filled with water and some hydrochloric acid. A small stirring rod spins around in the flask. After an hour, the amount of riboflavin and iron dissolved in the solution is measured. At least 75% of the riboflavin or iron must be dissolved in order for the supplement to be considered bioavailable. Other index vitamins include pyridoxine (B6), niacin, thiamine hydrochloride (B1), and ascorbic acid (vitamin C). Other index minerals include calcium, zinc, and magnesium.
Having just learned one of the ways that the USP may measure dissolution and hence bioavailability, you probably feel really disappointed. Don’t worry because you are not alone. Critics of the USP approaches have clearly indicated that spinning a vitamin pill in a flask does not mimic digestion and absorption of the human GI tract. Nor does it consider all of the interactions between nutrients for absorption. Other options to study nutrient absorption that have been proposed are the use of animal models and cell cultures. Animal models are often criticized because they are too time consuming, too costly, or just too different to be of any use for applying to humans. A cell culture model has been designed using a line of cells from the colon. These cancer colon cells are called CaCo-2 cells. They are receiving a great deal of attention as the gold standard for the in vitro studying of nutrient absorption. Of course they have limitations as well, one being that most absorption of nutrients takes place in the small intestine, not the large intestine. There doesn’t appear to be any studies comparing CaCo-2 versus small intestine cells, so we don’t know exactly how useful they are. Still many scientists feel they are good enough for studying nutrient absorption.
Bioavailability: Some Final Thoughts
As I was at the conference on bioavailability, I noticed that many people had lots of questions. Supplement company reps wanted clear guidelines so they could produce quality products, government organizations wanted clear guidelines so they knew what to enforce, and scientists wanted clear guidelines so they knew what to study. The idea behind the conference was to come up with a research agenda. It seems like that goal was achieved. Although I think many people walked away more educated, I also think they were more confused than ever. The reason for the confusion is that there are many factors to consider, and thus far a consensus has not been reached. Now you are can understand the dilemma and are armed with knowledge of the factors involved in determining bioavailability. The next time a supplement ad promises greater absorption, you should be able to ask about excretion and uptake by the tissues. If an ad promises greater bioavailability, you should question how the company can promise it when top experts can’t even agree upon a single definition.
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